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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_47_библиотеки_им_акад_М_И_Перельмана
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426
Increase SA of
liver associated
enzymes
without
hyperbilirubine-
mia
(anicteric
hepatitis or
anicteric
cholestatic
hepatitis)
isoniazid
antiretroviral agents
methotrexate, tacrine,
aspirin,
acetaminophen
2 to 48weeks. Usually asymptomatic
No jaundice
Bilirubin <2.5mg/
dL
□ see acute and chronic
hepatitis phenotypes
Spontaneous
decrease of AST
and ALT SA into
the normal range
(i.e., adaptation) or
in association with
the decrease or
discontinuation of
agent within
4weeks.
Pure and bland
cholestasis
estrogens and
anabolic steroids,
azathioprine,
mercaptopurine
4 to 24weeks Pruritus and jaundice Variable increases
in AP and ALT SA
Bilirubin >2.5mg/
dl
Intrahepatic cholestasis with
minimal inammation or
hepatocellular necrosis.
Slow recovery,
over 4weeks
Acute fatty liver
with lactic
acidosis
aluridine
a
zidovudine,
didanosine, stavudine,
tetracycline
intravenous linezolid
7–28days Prodrome from
1–4weeks.
Shortness of breath and
weakness are
experienced when lactic
acidosis appears,
followed by stupor and
coma.
Jaundice is mild.
Increase in serum
lactate,
Increase in AST and
ALT over 2x ULN
Microvesicular steatosis Fatal
Table 14.2 (continued)
Clinical
Phenotype
Typical
agents Latency Clinical manifestations
Type of liver
prole
Liver
histology
Duration of liver
injury/
prognosis
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Fatty liver
(AKA
nonalcoholic
fatty liver
disease)
methotrexate,
tamoxifen
3 to 12months
to years
Absent or non-specic
for liver disease
Mild increase in
AST and ALT SA
Steatosis, ballooning
hepatocyte degeneration
Resolution or
decrease in SA of
liver associated
enzymes over time
after
discontinuation of
agent
Chronic
hepatitis
Isoniazid,
propylthiouracil,
nitrofurantoin,
minocylcine, brates,
statins, hydralazine
and methyldopa
Weeks or
months
Absent or non-specic
symptoms including
fatigue
Hepatocellular or
cholestatic of at
least 6months
duration.
Autoantibodies may
be present
Portal inammation, spotty
lobular inammation and
necrosis, interface hepatitis,
and portal brosis.
Chronic or slow
resolution of acute
injury
Sinusoidal
obstruction
syndrome
Chemotherapeutic
agents including
busulfan,
vinca alkaloids,
cyclophosphamide,
melphalan,
carmustine thiotepa,
dacarbazine,
carboplatin, cisplatin,
and oxaliplatin
Acute: 1 to
3weeks
Subacute or
chronic:
Months and
years
Typical manifestation is
1) Tender
hepatomegaly, 2)
sudden weight gain
(>2% of body weight)
From uid retention,
and ascites
Increase in AST and
ALT SA and
bilirubin
concentration
Acute: Dilation of sinusoids
and extravasation of red blood
cells into the space of Disse.
Subacute: Collagen deposition
in sinusoids and small hepatic
veins with further congestion,
centrolobular necrosis, and
apparent occlusion of hepatic
venules.
Chronic: Extensive
collagenization of sinusoids
and venules [107]
Can be severe and
lead to acute liver
failure.
Patients can
recover, they can
also progress to
cirrhosis and its
complications
(continued)
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Nodular
regenerative
hyperplasia
Azathioprine,
thioguanine,
mercaptopurine,
didanosine, stavudine,
isoplatin,
vitamin A
1 to 6years;
occasionally
within
6months
Fatigue and symptoms
of liver disease and
hepatic synthetic
dysfunction
Mild increase in
AST and ALT SA
Regenerative nodules with
minimal or no brosis
Complications of
portal hypertension
Liver tumors
and cancer
Estrogens,
Thorotrast
b
,
Androgenic steroids
Chronic intake
of agents
Liver mass:
Adenomata,
Angiosarcoma
Liver prole may
be normal or
cholestatic, from
SOL
Characteristic of the type of
tumor
Depending on the
type of tumor and
stage.
Immunoallergic
hepatitis
sulfonamides,
penicillins,
macrolides,
uoroquinolones,
nevirapine, efavirenz,
allopurinol, or
aromatic
anticonvulsants.
Short, within
8weeks, but as
short as 1 to
2days,
especially with
reexposure
Fever, arthralgias, rash,
eosinophilia.
DRESS syndrome
(drug reaction with
eosinophilia and
systemic symptoms)
can be associated with
this type of hepatitis
Mixed or
cholestatic pattern
with increased AST
and ALT and AP
SA.
Eosinophilia.
Hepatocellular necrosis and
hepatic eosinophils
Cholestatic forms
may evolve into
vanishing bile duct
syndrome
Table 14.2 (continued)
Clinical
Phenotype
Typical
agents Latency Clinical manifestations
Type of liver
prole
Liver
histology
Duration of liver
injury/
prognosis
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Autoimmune
hepatitis
methyldopa
nitrofurantoin
minocycline
hydralazine
fenobrate
alpha and beta
interferon, iniximab,
and etanercept
NSAIDs,
azathioprine, and
herbals supplements
2months to
years
Hepatocellular Hepatocellular
pattern, high serum
[IgG] and
autoimmune
markers.
Usually resolves in
association with
discontinuation of
the agent
Hepatocellular necrosis with
plasma cells and interface
hepatitis
Discontinuation of
the agent tends to
be associated with
resolution of the
hepatitis over a
month. Treatment
with corticosteroids
tends to be
effective. Absence
of relapse upon
discontinuation of
corticosteroids
supports the
diagnosis of
drug-induced
autoimmune
hepatitis [108]
Immune-
mediated
hepatitis
Checkpoint inhibitors
including nivolumab
and Atezolizumab
[86]
One to three
months
Fatigue and pruritus.
May be associated with
systemic manifestations
Hepatocellular and
mixed
Focal or conuent necrosis
associated with lymphocytic
(i.e., activated T cells) [85]
Discontinuation of
the agent and
intravenous
steroids with oral
tapering over
30days
(continued)
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Granulomatous
hepatitis
allopurinol
carbamazepine
methyldopa
phenytoin
quinidine
sulphonamides
etanercept [109]
kratom [
110]
Undetermined;
4 to 24weeks
documented
for some drugs
Asymptomatic or
fatigue and pruritus in
cases of acute injury
Mixed or
cholestatic
Noncaseous granulomata with
eosinophils in early phases,
especially in association with
plasma cells on continuous
exposure to the agent [
84]
Recovery tends to
follow drug
withdrawal [111]
Acute liver
failure
diclofenac
isoniazid
troglitazone
telithromycin
Days to up to
6months
Prodrome of fatigue
and inappetence,
jaundice, and choluria,
and altered mental
status
Predominantly
hepatocellular,
modest cholestasis,
and synthetic
dysfunction □
Conuent hepatocellular
necrosis with marked
inammatory activity, or
without inammation in the
case of acetaminophen,
cocaine, 3,4-methylenedioxy-
methylamphetamine (MDMA)
[
112]
May be fatal and
require liver
transplantation
NAC associated
with improved
transplant free
survival
Vanishing bile
duct syndrome
amoxicillin-
clavulanate, NSAIDs
sulfonamides
aromatic
anticonvulsants
Pruritus Cholestatic pattern
and accompanied
features of
cholestasis
including
hyperlipidemia in
chronicity
Bile duct injury and
hepatocellular damage in early
stages. Ductopenia and bile
ductular proliferation.
Cirrhosis in late stages [112].
May resolve.
Ductopenia and
biliary cirrhosis
and liver failure
may develop.
Table 14.2 (continued)
Clinical
Phenotype
Typical
agents Latency Clinical manifestations
Type of liver
prole
Liver
histology
Duration of liver
injury/
prognosis
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Cirrhosis methyldopa
amiodarone
valproate
methotrexate
Considered
from chronic
(i.e., years)
exposure to an
agent probably
from ongoing
hepatitis or
steatosis
Fatigue, pruritus,
sarcopenia,
complications of
end-stage liver disease
Modest increase
AST, ALT, and AP
SA.
Thrombocytopenia,
from splenomegaly
a reection of portal
hypertension
Nodules Complications of
cirrhosis
Latency: the time from initiation of agent to onset of clinical manifestations
ALT alanine amino transferase, AST aspartate amino transferase, SA serum activity, AP alkaline phosphatase, GGTP gamma glutamyl transpeptidase, ULN
upper limits of normal, AKA also known as, NSAIDs nonsteroidal anti-inammatory drugs, SOL space occupying lesions
Hepatocellular pattern refers to the predominance of elevation of SA of AST and ALT
Cholestatic pattern refers to the predominance of elevation of SA of AP and GGTP
□ no robust information available
□ coagulopathy and low albumin
a
: not in use
b
: contrast agent for radiographic studies not in use
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Laboratory Exams
The pattern of liver injury has been classied as hepatocellular, cholestatic, or mixed
hepatocellular and cholestatic. The R ratio is used to examine the probability of the
type of liver injury, but it is not an exact determinant; it is clinical judgment and a
good history that form the basis for a diagnosis of DILI.The R ratio is calculated as
multiples of the upper limit of normal (ULN) for the given enzyme. The clinical
phenotypes of DILI are shown in Table14.2.
Hepatocellular injury is dened as an SA of ALT and AST, respectively more
than ten times the ULN, with modest increases in SA of AP and gamma glutamyl
transpeptidase (GGTP). An R ratio of ALT to AP of at least ve denes the hepato-
cellular type of injury (Table14.2).
Cholestatic liver injury is characterized by increased SA of AP and GGTP with
minimal or modest increases of ALT and AST SAs. An R ratio of ALT to AP up to
2 denes cholestatic liver injury. The bilirubin may be high (Table14.2).
Two types of DILI require particular attention because of their distinct features:
granulomatous hepatitis and DILI secondary to immunotherapy, including check-
point inhibitors.
Granulomatous hepatitis was reported as the least common type of histological
injury pattern of DILI, 2.6%, in a retrospective study comprised of thirty-eight cases
[83]. Granulomatous hepatitis has been reported in 5 to 10% of liver biopsy sam-
ples, with tuberculosis and sarcoidosis being considered the most common causes.
A retrospective review documented 6% of cases of granulomatous hepatitis from
1500 cases obtained over ten years, with 29% of the cases being attributed to medi-
cations as a cause, including antihypertensive, antirheumatic, anticonvulsant, and
antimicrobial agents [84] (Table14.2).
DILI secondary to immunotherapy has emerged as a unique complication in the
treatment of patients with cancer with this relatively new therapy of checkpoint
inhibitors [86] and with other immunomodulators [85], including nivolumab [85,
86] (Table14.2).
The most common pattern of DILI is a mixed liver prole, with hepatocellular
and cholestatic features. The R ratio is between 2 and 5 (Table14.2).
Imaging Studies
A liver sonogram provides information on the liver architecture, including fat depo-
sition, blood ow, space occupying lesions, and aspects of biliary obstruction,
including intra and extrahepatic. The addition of Doppler studies increases the
information regarding blood ow [2].
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Computed tomography and magnetic resonance imaging (MRI) add information
regarding the hepatic parenchyma and liver masses’ characterization. The MRI is an
excellent test to examine the intra and extrahepatic bile ducts, including strictures
and dilatations [2].
Liver Histology
A liver biopsy is not fundamental in the diagnosis of DILI, but it can help in the
presence of comorbidities, confounding factors, and uncertain diagnosis. The deci-
sion to do a liver biopsy should always be individualized according to the risks
versus benets of the information from the procedure. The ndings of liver histol-
ogy versus the type of liver injury are reported in Table14.2.
The histological ndings associated with mild or moderate liver injury are granu-
lomata and eosinophils, in contrast to neutrophil inltration, marked necrosis and
brosis, marked cholestasis in association with bile ductular proliferation, portal
venopathy, and microvesicular steatosis, which are associated with severe liver
injury, liver transplantation, or death [33].
Natural History
DILI can present with acute liver failure (ALF) [2, 87]; accordingly, extreme efforts
must be made to identify the drug and discontinue it. ALF is the rapid onset of
hepatic synthetic dysfunction and hepatic encephalopathy in the absence of prior
liver disease [88]. ALF is associated with high morbidity and mortality [88].
A sixteen-year prospective study of ALF from the United States from 1998 to
2013 enrolled 2070 patients, 69% of whom were women. DILI was the cause of
ALF in 57.1%, 46.3% of which was due to acetaminophen hepatotoxicity, mostly
due to accidental overdose, and 10.8% to other agents. Three notable observations
were made from that study: admission to the intensive care unit increased, the use
of N-acetylcysteine was not limited to acetaminophen induced ALF, and there was
an increase in transplant-free survival and a decrease in liver transplantation listings
for all causes of ALF, being statistically signicant for ALF from acetaminophen
induced DILI and other DILI cases [87].
Twenty-eight patients with a mean age of 55 years, 18 (62%) of whom were
women comprised 5.7 of the 493 cases of idiosyncratic DILI reported to the Spanish
registry. This group exhibited chronic changes on follow up of up to 20months.
Their liver panel was still abnormal at 3 months after discontinuing the drug associ-
ated with DILI for the hepatocellular phenotype of DILI, or more than 6 months
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after a cholestatic and mixed pattern of injury [89]. The most common drug classes
implicated in the DILI event associated with chronicity were cardiovascular, 28.5%,
and central nervous system agents, 25%, compared to their proportions in the whole
DILI database, 9.8%, and 13%, respectively [89]. The most common drugs associ-
ated with DILI were amoxicillin-clavulanate, bentazepam, atorvastatin, and capto-
pril. Nine percent of the patients with cholestatic and mixed DILI progressed to
chronicity versus the 4% of hepatocellular cases, which signicantly differed. Three
of the patients with hepatocellular injury progressed to cirrhosis and two to chronic
hepatitis. One with cholestatic and mixed injury progressed to cirrhosis, and three
had documented bile duct lesions on liver histology. These data suggested that
although cholestatic and mixed DILI are associated with chronicity more com-
monly than the hepatocellular type, the progression of the latter is of increased
severity, i.e. cirrhosis [89].
A group of 59 patients, with a median age of 62years (range 42–71) and a mean
follow up of 48weeks (range 26–96) post the DILI event, were evaluated in a clinic
in Sweden. Prior to the DILI episode, nine patients had chronic liver disease from
which progression was not documented on follow up. Three of the 50 (6%) without
chronic liver disease had persistently abnormal liver panel not explained by another
liver disease; they had been exposed to nitrofurantoin, clindamycin, and ucloxacil-
lin, with the last two drugs having been associated with hyperbilirubinemia during
the DILI occurrence. The diagnoses made de novo in patients who continued to have
abnormal liver tests were nonalcoholic fatty liver disease in three and alcoholic liver
disease in one. These results were interpreted to suggest that chronic liver abnor-
malities are uncommon long term in patients who recover from DILI [90]. However,
another follow-up study from the same group reported outcomes in patients who had
experienced DILI in association with hyperbilirubinemia to the Swedish Adverse
Drug Reaction Advisory Committee from 1970 to 2004. This group of patients had
survived the DILI event and could be linked to the Swedish Hospital Discharge and
Cause of Death Registries. From the accessed group comprised of 685 patients, 23
(3.4%) had been hospitalized for liver disease, and 5 had liver related mortality, in
whom the duration of treatment with the DILI implicated agent had been prolonged,
135days, compared to those in whom liver related morbidity and mortality were not
documented, 53days, both signicantly different. Autoimmune hepatitis was diag-
nosed in ve of the 23 patients (22%) after a mean of 5.8years of the DILI episode.
Thus, although not common, liver disease with important detrimental consequences
can develop after DILI in association with jaundice. A role of DILI in the triggering
of subsequent hepatic complications was considered [91].
Most DILI cases from checkpoint inhibitors are reported to resolve after the trig-
gering agent’s discontinuation and treatment with steroids. Deaths have been
reported in patients who have DILI in association with systemic complications and
in whom there was a delay in treatment with steroids [85]. The guidelines from the
EASLD provide recommendations on the management of immune-mediated liver
injury from this type of drug [33].
The reintroduction of an agent after documented DILI, i.e., rechallenge, is con-
troversial [33]. In cases of nonessential medications, this practice should be avoided.
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In the context of cancer therapy, when the drug’s benets outweigh its risk for caus-
ing DILI, the expertise from internists, hepatogastroenterologists, and oncologists
in concert with the will of the patient and information from the pharmaceutical
companies is required. In the context of clinical trials, the advisory board should be
involved. As pharmaco-oncology is fortunately an area of continuous growth,
updated guidelines and the LiverToxNIH.gov website should be a frequently
accessed recourse [2].
Associated Conditions
The most common organs involved in the drug rash with eosinophilia and systemic
symptoms (DRESS syndrome) is the liver and the skin, thus being part of the DILI
spectrum and associated with substantial morbidity [92]. Removal of the implicated
agent and steroids is the standard treatment [93]
Treatment
The treatment of DILI is the immediate discontinuation of the suspected agent,
providing supportive care, managing symptoms of pruritus, and evaluating for liver
transplantation in liver failure cases, thus requiring close communication with a
liver transplant center and early referral.
Acetaminophen overdose is treated with oral charcoal to prevent its absorption
when the ingestion is documented three to four hours before the presentation.
N-acetylcysteine is a modied amino acid [88], which has been extended as a treat-
ment for ALF from causes other than acetaminophen toxicity [87]. Cysteine has
antioxidant activity and is required to synthesize glutathione, an essential intracel-
lular antioxidant, protecting against free radicals and other intracellular toxins such
as intermediates of drug metabolism. Glutathione is depleted in patients with acet-
aminophen overdose leading to the formation of toxic adducts of acetaminophen
metabolites with essential intracellular molecules [94].
In the context of ALF, the use of steroids is not the standard, including ALF from
DILI; however, EASLD guidelines on DILI state: “in idiosyncratic DILI, routine
use of corticosteroids treatment may not be substantiated” [33], which may leave
room for their use. In a retrospective study that included 361 patients with ALF, 131
of whom had ALF from DILI, steroids were associated with what was considered a
marginal benecial effect on spontaneous survival, 35% versus 23%, but the effect
was not sustained after multivariable analysis of the data [95]. The use of steroids
and ursodeoxycholic acid in a group of ten patients with severe DILI was reported
to decrease the SA of transaminases and bilirubin concentration by half within two
weeks of treatment. Steroid therapy was tapered, and ursodeoxycholic acid was
continued for several weeks [96].
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